Vesicular Monoamine Transporter-2 Ligands and Their Use in the Treatment of Psychostimulant Abuse

ABSTRACT

The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. application Ser. No. 15/493,836, filed Apr. 21, 2017, which claims the benefit of U.S. Provisional Application No. 62/325,875, filed Apr. 21, 2016, both of which applications are herein incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering N-phenylalkyl amphetamine derivatives and pharmaceutical compositions containing these compounds to an individual in need thereof.

BACKGROUND OF THE INVENTION

The action of many therapeutic neuropharmacological agents involve the modulation of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) release, uptake and storage within their respective terminals in the central nervous system (CNS). Most neurotransmitters are stored in synaptic vesicles, which are prominent features of nerve terminals. Sequestration into vesicles appears to be responsible for maintaining a ready supply of neurotransmitter molecules available for neuronal exocytotic release into the synaptic cleft. Vesicles also serve the role of protecting the neurotransmitter molecules from metabolic breakdown. One transport site on the vesicle membrane is the vesicular monoamine transporter-2 (VMAT2), whose role is to transport transmitters from the cytosol into the synaptic vesicle. Once the neurotransmitter is released from the terminal into the synaptic space, it interacts with postsynaptic receptors and subsequently is taken back up into the terminal via the plasma membrane transporter (e.g., DAT and/or the serotonin transporter [SERT]). Thus, transporter proteins modify the concentration of neurotransmitters in the cytosolic and vesicular storage pools, and thereby have the ability to alter subsequent neurotransmission.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

-   -   wherein     -   m is an integer in the range from 1 to 3;     -   n is zero or an integer in the range from 1 to 5;     -   R₁ and R₂ are independently an aryl group or a heteroaryl group         which may be substituted by one or more substituents;     -   wherein substituents on R₁ and R₂ are independently selected         from the group consisting of mono-, di-, or tri-tritium; methyl;         deuteroinethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl;         isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆         cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical         forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated         hydrocarbon ring; a nitrogen containing heterocyclic or         heteroaryl moiety; an oxygen containing heterocyclic or         heteroalkyl moiety; a sulfur containing heterocyclic or         heteroaryl moiety; a selenium containing heterocyclic or         heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety         containing at least two atoms selected from the group consisting         of nitrogen, oxygen, and sulfur; ortho-, meta-, or         para-substituted benzenephenyl; phenylethyl; amino;         cycloalkylamine, isopropylamino; N-methylamino;         N,N-dimethylamino; carboxylate; methylcarboxylate;         ethylcarboxylate; propylcarboxylate; isopropylcarboxylate;         carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano;         aminomethyl; N-methylaminonmethyl; N,N-dimethylaminomethyl;         carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide;         acetyl; propionyl; fonnyl; benzoyl; sulfate; phenyl;         methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy;         propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol;         fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl;         propargyl; nitro; carbamoyl; ureido; azido; isocyanate;         thioisocyanate; hydroxylamino; nitrile; a saturated or         unsaturated hydrocarbon ring; a nitrogen containing heterocyclic         or heteroaryl moiety; an oxygen containing heterocyclic or         heteroryl moiety; a sulfur containing heterocyclic or heteroaryl         moiety; a selenium containing heterocyclic or heteroaryl moiety;         a mixed heterocyclic or heteroaryl moiety containing at least         two atoms selected from the group consisting of nitrogen, oxygen         and sulfur; and ortho-, meta-, or para-substituted benzene,     -   wherein one or more of the benzyl; phenyl; saturated or         unsaturated hydrocarbon ring; nitrogen containing heterocyclic         or heteroaryl moiety; oxygen containing heterocyclic or         heteroaryl moiety; sulfur containing heterocyclic or heteroaryl         moiety; selenium containing heterocyclic or heteroaryl moiety;         mixed heterocyclic or heteroaryl moiety containing at least two         atoms selected from the group consisting of nitrogen, oxygen and         sulfur; or ortho-, meta-, or para-substituted benzene         substituent on R₁ or R₂ may be independently fused to R₁ or R₂         or linked to R₁ or R₂;     -   R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl;         2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl;         1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl;         N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl;         N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl;         1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl         substituted with one or more fluoro; or benzyl;     -   R₄ is a hydrogen atom; a methyl, ethyl, propyl, isopropyl, or         carbonyl group; or a methyl, ethyl propyl or isopropyl group         substituted with a hydroxyaryl group; and     -   R₅ is hydrogen or methyl; or     -   an enantiomer; racemate; or pharmaceutically acceptable salt         thereof.

The present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable additive:

-   -   wherein     -   m is an integer in the range from 1 to 3;     -   n is zero or an integer in the range from 1 to 5;     -   R₁ and R₂ are independently an aryl group or a heteroaryl group         which may be substituted by one or more substituents;     -   wherein substituents on R₁ and R₂ are independently selected         from the group consisting of mono-, di-, or tri-tritium; methyl;         deuteromethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl;         isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆         cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical         forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated         hydrocarbon ring; a nitrogen containing heterocyclic or         heteroaryl moiety; an oxygen containing heterocyclic or         heteroaryl moiety; a sulfur containing heterocyclic or         heteroaryl moiety; a selenium containing heterocyclic or         heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety         containing at least two atoms selected from the group consisting         of nitrogen, oxygen, and sulfur; ortho-, meta-, or         para-substituted benzenephenyl; phenylethyl; amino;         cycloalkylamine, isopropylamino; N-methylamino;         N,N-dimethylamino; carboxylate; methylcarboxylate;         ethylcarboxylate; propylcarboxylate; isopropylcarboxylate;         carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano;         aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl;         carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide;         acetyl; propionyl; formyl; benzoyl; sulfate; phenyl;         methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy;         propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol;         fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl;         propargyl; nitro; carbamoyl; ureido; azido; isocyanate;         thioisocyanate; hydroxylamino; nitrile; a saturated or         unsaturated hydrocarbon ring; a nitrogen containing heterocyclic         or heteroaryl moiety; an oxygen containing heterocyclic or         heteroaryl moiety; a sulfur containing heterocyclic or         heteroaryl moiety; a selenium containing heterocyclic or         heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety         containing at least two atoms selected from the group consisting         of nitrogen, oxygen and sulfur; and ortho-, meta-, or         para-substituted benzene,     -   wherein one or more of the benzyl; phenyl; saturated or         unsaturated hydrocarbon ring; nitrogen containing heterocyclic         or heteroaryl moiety; oxygen containing heterocyclic or         heteroaryl moiety; sulfur containing heterocyclic or heteroaryl         moiety; selenium containing heterocyclic or heteroaryl moiety;         mixed heterocyclic or heteroaryl moiety containing at least two         atoms selected from the group consisting of nitrogen, oxygen and         sulfur; or ortho-, meta-, or para-substituted benzene         substituent on R₁ or R₂ may be independently fused to R₁ or R₂         or linked to R₁ or R₂;     -   R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl;         2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl;         1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl;         N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl;         N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl;         1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl         substituted with one or more fluoro; or benzyl;     -   R₄ is a hydrogen atom; a methyl, ethyl, propyl, isopropyl, or         carbonyl group; or a methyl, ethyl propyl or isopropyl group         substituted with a hydroxyaryl group; and     -   R₅ is hydrogen or methyl; or     -   an enantiomer; racemate; or pharmaceutically acceptable salt         thereof.

The present invention provides a method of treating a substance use disorder, drug dependence/abuse or withdrawal from drug dependence/abuse in an individual in need thereof, wherein the method comprises the step of administering to the individual a compound of formula (I):

-   -   wherein     -   m is an integer in the range from 1 to 3;     -   n is zero or an integer in the range from 1 to 5;     -   R₁ and R₂ are independently an aryl group or a heteroaryl group         which may be substituted by one or more substituents;     -   wherein substituents on R₁ and R₂ are independently selected         from the group consisting of mono-, di-, or tri-tritium; methyl;         deuteroinethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl;         isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆         cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical         forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated         hydrocarbon ring; a nitrogen containing heterocyclic or         heteroaryl moiety; an oxygen containing heterocyclic or         heteroaryl moiety; a sulfur containing heterocyclic or         heteroaryl moiety; a selenium containing heterocyclic or         heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety         containing at least two atoms selected from the group consisting         of nitrogen, oxygen, and sulfur; ortho-, meta-, or         para-substituted benzenephenyl; phenylethyl; amino;         cycloalkylamine, isopropylamino; N-methylamino; N,N         dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate;         propylcarboxylate; isopropylcarboxylate; carboxaldehyde;         acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl;         N-methylaminomnethyl; N,N-dimethylaminomethyl; carboxamide;         N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl;         fonnyl; benzoyl; sulfate; phenyl; methylsulfate; hydroxyl;         methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol;         methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo;         trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl;         ureido; azido; isocyanate; thioisocyanate; hydroxylamino;         nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen         containing heterocyclic or heteroaryl moiety; an oxygen         containing heterocyclic or heteroaryl moiety; a sulfur         containing heterocyclic or heteroaryl moiety; a selenium         containing heterocyclic or heteroaryl moiety; a mixed         heterocyclic or heteroaryl moiety containing at least two atoms         selected from the group consisting of nitrogen, oxygen and         sulfur; and ortho-, meta-, or para-substituted benzene,     -   wherein one or more of the benzyl; phenyl; saturated or         unsaturated hydrocarbon ring; nitrogen containing heterocyclic         or heteroaryl moiety; oxygen containing heterocyclic or         heteroaryl moiety; sulfur containing heterocyclic or heteroaryl         moiety; selenium containing heterocyclic or heteroaryl moiety;         mixed heterocyclic or heteroaryl moiety containing at least two         atoms selected from the group consisting of nitrogen, oxygen and         sulfur; or ortho-, meta-, or para-substituted benzene         substituent on R₁ or R₂ may be independently fused to R₁ or R₂         or linked to R₁ or R₂;     -   R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl;         2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl;         1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl;         N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl;         N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl;         1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl         substituted with one or more fluoro; or benzyl;     -   R₄ is a hydrogen atom; a methyl, ethyl, propyl, isopropyl, or         carbonyl group; or a methyl, ethyl, propyl or isopropyl group         substituted with a hydroxyaryl group; and     -   R₅ is hydrogen or methyl; or     -   an enantiomer; racemate; or pharmaceutically acceptable salt         thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I):

-   -   wherein     -   m is an integer in the range from 1 to 3;     -   n is zero or an integer in the range from 1 to 5;     -   R₁ and R₂ are independently an aryl group or a heteroaryl group         which may be substituted by one or more substituents;     -   wherein substituents on R₁ and R₂ are independently selected         from the group consisting of mono-, di-, or tri-tritium; methyl;         deuteromethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl;         isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆         cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical         forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated         hydrocarbon ring; a nitrogen containing heterocyclic or         heteroaryl moiety; an oxygen containing heterocyclic or         heteroaryl moiety; a sulfur containing heterocyclic or         heteroaryl moiety; a selenium containing heterocyclic or         heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety         containing at least two atoms selected from the group consisting         of nitrogen, oxygen, and sulfur; ortho-, meta-, or         para-substituted benzenephenyl; phenylethyl; amino;         cycloalkylamine, isopropylamino; N-methylamino;         N,N-dimethylamino; carboxylate; methylcarboxylate;         ethylcarboxylate; propylcarboxylate; isopropylcarboxylate;         carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano;         aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl;         carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide;         acetyl; propionyl; formyl; benzoyl; sulfate, phenyl;         methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy;         propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol;         fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl;         propargyl; nitro; carbamoyl; ureido; azido; isocyanate;         thioisocyanate; hydroxylamino; nitrile; a saturated or         unsaturated hydrocarbon ring; a nitrogen containing heterocyclic         or heteroaryl moiety; an oxygen containing heterocyclic or         hetetoaryl moiety; a sulfur containing heterocyclic or         heteroaryl moiety; a selenium containing heterocyclic or         heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety         containing at least two atoms selected from the group consisting         of nitrogen, oxygen and sulfur; and ortho-, meta-, or         para-substituted benzene,     -   wherein one or more of the benzyl; phenyl; saturated or         unsaturated hydrocarbon ring; nitrogen containing heterocyclic         or heteroaryl moiety; oxygen containing heterocyclic or         heteroaryl moiety; sulfur containing heterocyclic or heteroaryl         moiety; selenium containing heterocyclic or heteroaryl moiety;         mixed heterocyclic or heteroaryl moiety containing at least two         atoms selected from the group consisting of nitrogen, oxygen and         sulfur; or ortho-, meta-, or para-substituted benzene         substituent on R₁ or R₂ may be independently fused to R₁ or R₂         or linked to R₁ or R₂;     -   R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl;         2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl;         1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl;         N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl;         N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl;         1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl         substituted with one or more fluoro; or benzyl;     -   R₄ is a hydrogen atom; a methyl, ethyl propyl, isopropyl, or         carbonyl group; or a methyl, ethyl propyl or isopropyl group         substituted with a hydroxyaryl group; and     -   R₅ is hydrogen or methyl; or an enantiomer; racemate; or         pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein

-   -   wherein     -   m is 1;     -   n is 2;     -   R₁ and R₂ are independently an aryl group or a heteroaryl group         which may be substituted by one or more substituents;     -   wherein substituents on R₁and R₂ are independently selected from         the group consisting of methyl; alkylsulfonyl; alkylsulfinyl; a         saturated or unsaturated hydrocarbon ring; a nitrogen containing         heterocyclic or heteroaryl moiety; a sulfur containing         heterocyclic or heteroaryl moiety; phenyl; amino;         cycloalkylamine; isopropylamino; N-methylamino;         N,N-dimethylamino; ethylcarboxylate; carboxamide;         N-methylcarboxamide; hydroxyl; methoxy; difluoromethoxy; thiol;         fluoro; chloro; bromo; iodo; trifluoromethyl; nitro; nitrile; a         saturated or unsaturated hydrocarbon ring; a nitrogen containing         heterocyclic or heteroaryl moiety; a sulfur containing         heterocyclic or heteroaryl moiety,     -   wherein one or more of the phenyl; saturated or unsaturated         hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl         moiety; sulfur containing heterocyclic or heteroaryl moiety         substituent on R₁ or R₂ may be independently fused to R₁ or R₂         or linked to R₁ or R₂;     -   R₃ is a methyl, ethyl, isopropyl, hydroxymethyl, or methyl         substituted with one or more fluoro; or benzyl; and     -   R₄ is a hydrogen atom; a carbonyl group; or a methyl, ethyl,         propyl or isopropyl group substituted with a hydroxyaryl group;         and     -   R₅ is hydrogen or methyl; or     -   an enantiomer; racemate; or pharmaceutically acceptable salt         thereof.

A further embodiment of the invention is a compound of formula (I), wherein: m is 1 or 2; and n is an integer from 1 to 5; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

An further embodiment of the invention is a compound of formula (I), wherein: m is 1 or 2; and n is an integer from 1 to 5; R₃ is methyl, ethyl, propyl, or isopropyl; and R₄ is a hydrogen atom or a methyl, ethyl, propyl, or isopropyl group; or an enantiomer, racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein: m is 1 or 2; and n is an integer from 1 to 5; wherein R₃ is methyl; and R₄ is a hydrogen atom or a methyl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (I), wherein m is 1; n is 1; R₁ and R₂ are each independently a phenyl group, wherein R₁ and R₂ are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of benzyl; amino; hydroxyl; methoxy; fluoro; and bromo; R₃ is methyl; and R₄ is a hydrogen atom or a methyl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; R₁ and R₂ are each independently a phenyl group, wherein R₁ and R₂ are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of benzyl; amino; hydroxyl; methoxy; fluoro; and bromo; R₃ is methyl; and R₄ is a hydrogen atom or a methyl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (I), wherein m is 2; n is 1; R₁ and R₂ are each independently a phenyl group, wherein R₁ and R₂ are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of methoxy and bromo; R₃ is methyl; and R₄ is a hydrogen atom; or an enantiomer racemate; or pharmaceutically acceptable salt thereof.

Yet another embodiment of the invention is a compound of formula (I), wherein m is 2; n is 2; R₁ and R₂ are each independently a phenyl group, wherein R₁ and R₂ are each independently unsubstituted or substituted by one or more methoxy groups; R₃ is methyl; and R₄ is a hydrogen atom or a methyl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Yet another embodiment of the invention is a compound of formula (I), wherein m is 1; n is an integer from 3 to 5; R₁ and R₂ are each independently a phenyl group, wherein R₁ and R₂ are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of methoxy and bromo; R₃ is methyl; and R₄ is a hydrogen atom; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Yet another embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; R₁ is an unsubstituted phenyl group; R₂ is a phenyl group substituted with a methoxy group; R₃ is methyl; and R₄ is a hydrogen atom; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein: m is 1 and n is 2; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and R₁ and R₂ are aryl groups; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; R₁ and R₂ are independently aryl or heteroaryl groups, at least one of which is independently substituted with methyl; alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; phenyl; amino; cycloalkylamine; isopropylamino; N-methylamino; N, N-dimethylamino; ethylcarboxylate; carboxamide; N-methylcarboxamide; hydroxyl; methoxy; difluoromethoxy; thiol; fluoro; chloro; bromo; iodo; trifluoromethyl; nitro; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; and a sulfur containing heterocyclic or heteroaryl moiety, wherein one or more of the phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂.

A further embodiment is a compound of formula (I), wherein R₁ is a pyridyl group; a pyrimidyl group; an unsubstituted phenyl; or a phenyl substituted with chloro, fluoro, bromo, difluoro, trifluoromethyl, methoxy, carboxamide, amino, pyridinyl, or nitro; and R₂ is a indolyl group; a pyridyl group; a pyrazolyl group; an imidazolyl group; a quinolinyl group; a methylpyrazolyl group; an unsubstituted phenyl; or a phenyl substituted with fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, carboxamide, methylcarboxamide, amine, aminoisopropyl, nitro, methylsulfonyl, methylsulfinyl, aminocyclobutyl, dimethylamino, ethylcarboxylate, pyrimidinyl, pyridinyl, indolyl, thiophene, or hydroxyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; R₁ and R₂ are aryl groups, at least one of which is independently substituted with amino; fluoro; a saturated or unsaturated hydrocarbon ring; or a nitrogen containing heterocyclic or heteroaryl moiety; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and at least one of R₁ and R₂ is a heteroaryl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and at least one of R₁ and R₂ is an aryl group fused with a heteroaryl group; or an enantiomer racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and at least one of R₁ and R₂ is a heteroaryl group fused with one or more additional heteroaryl groups; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and at least one of R₁ and R₂ is a heteroaryl group fused with an aryl group; or an enantiomer, racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein at least one of R₁ and R₂ is a heteroaryl group fused with or linked to an aryl group, wherein the aryl group is substituted with an alkyl, methoxy, or carbonyl group; or at least one of R₁ and R₂ is an aryl group fused with or linked to a heteroaryl group, wherein the heteroaryl group is substituted with an alkyl, methoxy, or carbonyl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and at least one of R₁ and R₂ is a nitrogen-containing heteroaryl group; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

A further embodiment of the invention is a compound of formula (I), wherein m is 1; n is 2; and at least one of R₁ and R₂ is a nitrogen-containing heteroaryl group fused with a phenyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

In an embodiment of formula (I), R₅ is hydrogen. In another embodiment of formula (I), R₅ is methyl.

Compounds of formula (I) include the following compounds:

1. m=1, n=1, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 2. m=1, n=1, R₁=Ph, R₂=Ph, R₃=Me, R₄=CH₃, R₅=H 3. m=1, n=1, R₁=4-BrPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 4. m=1, n=2, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 5. R—, m=1, n=2, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 6. S—, m=1, n=2, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 7. m=1, n=2, R₁=Ph, R₂=Ph, R₃=Me, R₄=CH₃, R₅=H 8. m=1, n=2, R₁=Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 9. R—, m=1, n=2, R₁=Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 10. S—, m=1, n=2, R₁=Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 11. m=1, n=2, R₁=4-BrPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 12. R—, m=1, n=2, R₁=4-BrPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 13. S—, m=4, u=2, R₁=4-BrPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 14. m=1, n=3, R₁=4-BrPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 15. m=1, n=3, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 16. m=1, n=2, R₁=4-BrPh, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 17. m=1, n=4, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 18. m=1, n=5, R₁=Ph, R₂=Ph, R₂=Me, R₄=H, R₅=H 19. m=1 n=1, R₁=Ph, R₂=PhO, R₃=Me, R₄=H, R₅=H 20. m=1, n=1, R₁=4-BrPh, R₂=PhO, R₃=Me, R₄=H, R₅=H 21. m=1, n=1, R₁=Ph, R₂=4-OHPh, R₃=Me, R₄=H, R₅=H 22. m=1, n=1, R₁=Ph, R₂=3,4-diBnOPh, R₃=Me, R₄=H, R₅=H 23. m=1, n=1, R₁=Ph, R₂=3,4-diOHPh, R₃=Me, R₄=H, R₅=H 24. m=1, n=1, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 25. m=1, n=1, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=CH₃, R₅=H 26. m=1, n=2, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 27. R—, m=1, n=2, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 28. S—, m=1, n=2, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 29. r=1, n=2, R₁=4-MeOPh, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 30. m=1, n=2, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=CH₃, R₅=H 31. m=2, n=1, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 32. m=2, n=2, R₁=4-MeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 33. m=2, n=1, R₁=4-MeOPh, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 34. m=2, n=1, R₁=4-MeOPh, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 35. m=1, n=1, R₁=4-OHPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 36. m=1, n=2, R₁=4-OHPh, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 37. m=1, n=2, R₁=4-OHPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 38. m=1, n=1, R₁=4-FPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 39. m=1, n=2, R₁=4-FPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 40. m=1, n=2, R₁=4-FPh, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 41. m=1, n=1, R₁=4-NO₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 42. m=1, n=2, R₁=4-NO₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 43. m=1, n=2, R₁=4-NO₂Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 44. m=1, n=1, R₁=4-NH₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 45. m=1, n=2, R₁=4-NH₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 46. m=1, n=2, R₁=3,4-diMeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 47. m=1, n=3, R₁=3,4-diMeOPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 48. m=2, n=1, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 49. m=2, n=1, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 50. m=2, n=2, R₁=Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 51. m=2, n=2, R₁=Ph, R₂=Ph, R₃=Me, R₄=CH₃, R₅=H 52. m=2, n=2, R₁=Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 53. m=2, n=2, R₁=4-MeOPh, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H. 54. m=1, n=2, R₁=4-CF₃Ph, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 55. m=1, n=2, R₁=4-FPh, R₂=1H-indol-5-yl, R₃=Me, R₄=H, R₅=H 56. m=1, n=2, R₁=4-FPh, R₂=1H-indol-5-yl, R₃=Me, R₄=H, R₅=H 57. m=1, n=2, R₁=4-MeOPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 58. m=1, n=2, R₁=4-MeOPh, R₂=4-NO₂Ph, R₃=Me, R₄=H, R₅=H 59. m=1, n=2, R₁=3,4-diFPh, R₂=4-NO₂Ph, R₃=Me, R₄=H, R₅=H 60. m=1, n=2, R₁=3,4-diFPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 61. m=1, n=2, R₁=3,4-diFPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 62. m=1, n=2, R₁=4-ClPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 63. m=1, n=2, R₁=4-ClPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 64. m=1, n=2, R₁=4-ClPh, R₂=4-NO₂Ph, R₃=Me, R₄=H, R₅=H 65. m=1, n=2, R₁=4-FPh, R₂=4-[NH(isopropyl)]Ph, R₃=Me, R₄=H, R₅=H 66. m=1, n=2, R₁=4-FPh, R₂=4-[Me(CO)NH]Ph, R₃=Me, R₄=H, R₅=H 67. m=1, n=2, R₁=4-FPh, R₂=4-[Me(CO)NH]Ph, R₃=Me, R₄=H, R₅=H 68. m=1, n=2, R₁=4-(pyrimidin-5-yl)Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 69. m=1, n=2, R₁=4-(pyrimidin-5-yl)Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 70. m=1, n=2, R₁=4-FPh, R₂=4-(NH—CHO)Ph, R₃=Me, R₄=H, R₅=H 71. m=1, n=2, R₁=4-FPh, R₂=4-(NH—CHO)Ph, R₃=Me, R₄=H, R₅=H 72. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 73. m=1, u=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 74. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=Me, R₄=CHO, R₅=H 75. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=Ph, R₃=Me, R₄=CHO, R₅=H 76. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=Ph, R₃=Me, R₄=CHO, R₅=H 77. m=1, u=2, R₁=4-(NH—CHO)Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 78. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 79. m=1, n=2, R₁=4-NH₂Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 80. m=1, n=2, R₁=4-NH₂Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 81. m=1, n=2, R₁=4-FPh, R₂=4-FPh, R₃=CF₂H, R₄=H, R₅=H 82. m=1, u=2, R₁=4-FPh, R₂=4-FPh, R₃=CF₂H, R₄=H, R₅=H 83. m=1, n=2, R₁=4-(pyridin-3-yl)Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 84. m=1, n=2, R₁=4-(pyridin-3-yl)Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 85. m=1, n=2, R₁=4-BrPh, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 86. m=1, u=2, R₁=4-BrPh, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 87. m=1, u=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 88. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 89. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 90. m=1, n=2, R₁=4-(NH—CHO)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 91. m=1, u=2, R₁=4-FPh, R₂=1H-indole-3-yl, R₃=Me, R₄=H, R₅=H 92. m=1, n=2, R₁=4-FPh, R₂=1H-indole-3-yl, R₃=Me, R₄=H, R₅=H 93. m=1, n=2, R₁=4-FPh, R₂=4-[NH(cyclobutyl)]Ph, R₃=Me, R₄=H, R₅=H 94. m=1, n=2, R₁=4-FPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 95. m=1, n=2, R₁=4-FPh, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 96. m=1, n=2, R₁=3,4-diFPh, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 97. m=1, n=2, R₁=3,4-diFPh, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 98. m=1, n=2, R₁=Ph, R₂=Ph, R₃=CH₂F, R₄=H, R₅=H 99. m=1, n=2, R₁=Ph, R₂=Ph, R₃=CH₂F, R₄=H, R₅=H 100. m=1, n=2, R₁=4-FPh, R₂=Ph, R₃=CH₂F, R₄=H, R₅=H 101. m=1, n=2, R₁=Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 102. m=1, n=2, R₁=Ph, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 103. m=1, n=2, R₁=4-NH₂Ph, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 104. m=1, n=2, R₁=4-NH₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 105. m=1, n=2, R₁=4-NH₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 106. m=1, n=2, R₁=4-NH₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 107. m=1, n=2, R₁=4-FPh, R₂=4-NH₂Ph, R₃=CH₂F, R₄=H, R₅=H 108. m=1, n=2, R₁=4-FPh, R₂=4-NH₂Ph, R₃=CH₂F, R₄=H, R₅=H 109. m=1, n=2, R₁=4-NH₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 110. m=1, n=2, R₁=4-NH₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 111. m=1, n=2, R₁=4-NH₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 112. m=1, n=2, R₁=4-NH₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 113. m=1, n=2, R₁=4-NO₂Ph, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 114. m=1, n=2, R₁=4-NO₂Ph, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 115. m=1, n=2, R₁=4-NO₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 116. m=1, n=2, R₁=4-NO₂Ph, R₂=Ph, R₃=Me, R₄=H, R₅=H 117. m=1, n=2, R₁=4-NO₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 118. m=1, n=2, R₁=4-NO₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 119. m=1, n=2, R₁=4-NO₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 120. m=1, n=2, R₁=4-NO₂Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 121. m=1, n=2, R₁=4-NO₂Ph, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 122. m=1, n=2, R₁=4-NO₂Ph, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 123. m=1, n=2, R₁=4-FPh, R₂=4-NO₂Ph, R₃=CH₂F, R₄=H, R₅=H 124. m=1, n=2, R₁=4-FPh, R₂=4-NO₂Ph, R₃=CH₂F, R₄=H, R₅=H 125. m=1, n=2, R₁=4-NO₂Ph, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 126. m=1, n=2, R₁=4-FPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 127. m=1, n=2, R₁=4-FPh, R₂=Ph, R₃=Me, R₄=H, R₅=H 128. m=1, n=2, R₁=4-FPh, R₂=4-pyridyl, R₃=CH₂OH, R₄=H, R₅=H 129. m=1, n=2, R₁=4-FPh, R₂=4-pyridyl, R₃=CH₂OH, R₄=H, R₅=H 130. m=1, n=2, R₁=4-FPh, R₂=1H-pyrazole-1-yl, R₃=CH₂OH, R₄=H, R₅=H 131. m=1, n=2, R₁=4-FPh, R₂=1H-pyrazole-1-yl, R₃=CH₂OH, R₄=H, R₅=H 132. m=1, n=2, R₁=4-FPh, R₂=1H-pyrazole-1-yl, R₃=Me, R₄=H, R₅=H 133. m=1, n=2, R₁=4-FPh, R₂=1H-pyrazole-1-yl, R₃=Me, R₄=H, R₅=H 134. m=1, n=2, R₁=4-FPh, R₂=1H-imidazole-1-yl, R₃=Me, R₄=H, R₅=H 135. m=1, n=2, R₁=4-FPh, R₂=1H-imidazole-1-yl, R₃=Me, R₄=H, R₅=H 136. m=1, n=2, R₁=4-FPh, R₂=Ph, R₃=isopropyl, R₄=H, R₅=H 137. m=1, n=2, R₁=4-FPh, R₂=4-MeSO₂Ph, R₃=CH₂F, R₄=H, R₅=H 138. m=1, n=2, R₁=4-FPh, R₂=4-MeSO₂Ph, R₃=Me, R₄=H, R₅=H 139. m=1, n=2, R₁=4-FPh, R₂=4-MeSO₂Ph, R₃=Me, R₄=H, R₅=H 140. m=1, n=2, R₁=4-FPh, R₂=4-BrPh, R₃=isopropyl, R₄=H, R₅=H 141. m=1, n=2, R₁=4-FPh, R₂=4-BrPh, R₃=isopropyl, R₄=H, R₅=H 142. m=1, n=2, R₁=4-FPh, R₂=4-pyridyl, R₃=CH₂F, R₄=H, R₅=H 143. m=1, n=2, R₁=4-FPh, R₂=4-pyridyl, R₃=CH₂F, R₄=H, R₅=H 144. m=1, n=2, R₁=4-FPh, R₂=4-MeSOPh, R₃=Me, R₄=H, R₅=H 145. m=1, n=2, R₁=4-FPh, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 146. m=1, n=2, R₁=4-FPh, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 147. m=1, n=2, R₁=4-FPh, R₂=4-FPh, R₃=CH₂OH, R₄=H, R₅=H 148. m=1, n=2, R₁=4-FPh, R₂=quinoline-4-yl, R₃=CH₂F, R₄=H, R₅=H 149. m=1, n=2, R₁=4-FPh, R₂=quinoline-4-yl, R₃=CH₂F, R₄=H, R₅=H 150. m=1, n=2, R₁=4-FPh, R₂=4-ClPh, R₃=CH₂F, R₄=H, R₅=H 151. m=1, n=2, R₁=4-FPh, R₂=4-ClPh, R₃=CH₂F, R₄=H, R₅=H 152. m=1, n=2, R₁=4-FPh, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 153. m=1, n=2, R₁=4-FPh, R₂=4-FPh, R₃=CH₂F, R₄=H, R₅=H 154. m=1, n=2, R₁=4-FPh, R₂=4-BrPh, R₃=CH₂OH, R₄=H, R₅=H 155. m=1, n=2, R₁=4-FPh, R₂=4-BrPh, R₃=CH₂OH, R₄=H, R₅=H 156. m=1, n=2, R₁=4-FPh, R₂=4-NMe₂Ph, R₃=Me, R₄=H, R₅=H 157. m=1, n=2, R₁=4-FPh, R₂=4-NMe₂Ph, R₃=Me, R₄=H, R₅=H 158. m=1, n=2, R₁=4-FPh, R₂=4-[EtO(CO)]Ph, R₃=Me, R₄=H, R₅=H 159. m=1, n=2, R₁=4-FPh, R₂=4-[EtO(CO)]Ph, R₃=Me, R₄=H, R₅=H 160. m=1, n=2, R₁=4-FPh, R₂=4-NO₂Ph, R₃=Me, R₄=H, R₅=H 161. m=1, n=2, R₁=4-FPh, R₂=4-NO₂Ph, R₃=Me, R₄=H, R₅=H 162. m=1, n=2, R₁=4-FPh, R₂=quinoline-4-yl, R₃=Me, R₄=H, R₅=H 163. m=1, n=2, R₁=4-FPh, R₂=quinoline-4-yl, R₃=Me, R₄=H, R₅=H 164. m=1, n=2, R₁=4-CF₃Ph, R₂=4-pyridyl, R₃=Me, R₃=H, R₅=H 165. m=1, n=2, R₁=4-CF₃Ph, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 166. m=1, n=2, R₁=4-FPh, R₂=4-(1-methyl-1H-pyrazol-5-yl)Ph, R₃=Me, R₄=H, R₅=H 167. m=1, n=2, R₁=4-FPh, R₂=4-(1-methyl-1H-pyrazol-5-yl)Ph, R₃=Me, R₄=H, R₅=H 168. m=1, n=2, R₁=4-pyridyl, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 169. m=1, n=2, R₁=4-pyridyl, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 170. m=1, n=2, R₁=4-(pyrimidin-5-yl)Ph, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 171. m=1, n=2, R₁=4-(pyrimidin-5-yl)Ph, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 172. m=1, n=2, R₁=4-pyridyl, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 173. m=1, n=2, R₁=4-pyridyl, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=H 174. m=1, n=2, R₁=4-BrPh, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 175. m=1, n=2, R₁=4-BrPh, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 176. m=1, n=2, R₁=4-FPh, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 177. m=1, n=2, R₁=4-FPh, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 178. m=1, n=2, R₁=4-pyridyl, R₂=4-OHPh, R₃=Me, R₄=H, R₅=H 179. m=1, n=2, R₁=4-pyridyl, R₂=4-OHPh, R₃=Me, R₄=H, R₅=H 180. m=1, n=2, R₁=4-BrPh, R₂=4-IPh, R₃=Me, R₄=H, R₅=H 181. m=1, n=2, R₁=4-BrPh, R₂=4-IPh, R₃=Me, R₄=H, R₅=H 182. m=1, n=2, R₁=4-FPh, R₂=4-IPh, R₃=Me, R₄=H, R₅=H 183. m=1, n=2, R₁=4-FPh, R₂=4-IPh, R₃=Me, R₄=H, R₅=H 184. m=1, n=2, R₁=4-BrPh, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 185. m=1, n=2, R₁=4-BrPh, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 186. m=1, n=2, R₁=4-pyridyl, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 187. m=1, n=2, R₁=4-pyridyl, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 188. m=1, n=2, R₁=4-FPh, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 189. m=1, n=2, R₁=4-FPh, R₂=4-ClPh, R₃=Me, R₄=H, R₅=H 190. m=1, n=2, R₁=4-FPh, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 191. m=1, n=2, R₁=4-FPh, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 192. m=1, n=2, R₁=4-(pyridin-3-yl)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 193. m=1, n=2, R₁=4-(pyridin-3-yl)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 194. m=1, n=2, R₁=Ph, R₂=4-CF₃Ph, R₃=Me, R₄=H, R₅=H 195. m=1, n=2, R₁=Ph, R₂=4-CF₃Ph, R₃=Me, R₄=H, R₅=H 196. m=1, n=2, R₁=4-(pyrimidin-5-yl)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 197. m=1, n=2, R₁=4-(pyrimidin-5-yl)Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 198. m=1, n=2, R₁=Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=Me 199. m=1, n=2, R₁=Ph, R₂=4-MeOPh, R₃=Me, R₄=H, R₅=Me 200. m=1, n=2, R₁=4-BrPh, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 201. m=1, n=2, R₁=4-BrPh, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 202. m=1, n=2, R₁=Ph, R₂=4-(pyrimidin-5-yl)Ph, R₃=Me, R₄=H, R₅=H 203. m=1, n=2, R₁=Ph, R₂=4-(pyrimidin-5-yl)Ph, R₃=Me, R₄=H, R₅=H 204. m=1, n=2, R₁=Ph, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 205. m=1, n=2, R₁=Ph, R₂=4-pyridyl, R₃=Me, R₄=H, R₅=H 206. m=1, n=2, R₁=Ph, R₂=4-(thiophen-2-yl)Ph, R₃=Me, R₄=H, R₅=H 207. m=1, n=2, R₁=Ph, R₂=4-OHPh, R₃=Et, R₄=H, R₅=H 208. m=1, n=2, R₁=Ph, R₂=4-OHPh, R₃=Et, R₄=H, R₅=H 209. m=1, n=2, R₁=4-CF₃Ph, R₂=4-OHPh, R₃=Me, R₄=H, R₅=H 210. m=1, n=2, R₁=Ph, R₂=4-(pyridin-3-yl)Ph, R₃=Me, R₄=H, R₅=H 211. m=1, n=2, R₁=Ph, R₂=4-(pyridin-3-yl)Ph, R₃=Me, R₄=H, R₅=H 212. m=1, n=2, R₁=Ph, R₂=4-IPh, R₃=Me, R₄=H, R₅=H 213. m=1, n=2, R₁=Ph, R₂=4-IPh, R₃=Me, R₄=H, R₅=H 214. m=1, n=2, R₁=Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 215. m=1, n=2, R₁=Ph, R₂=4-FPh, R₃=Me, R₄=H, R₅=H 216. m=1, n=2, R₁=Ph, R₂=4-SHPh, R₃=Me, R₄=H, R₅=H 217. m=1, n=2, R₁=Ph, R₂=4-SHPh, R₃=Me, R₄=H, R₅=H 218. m=1, n=2, R₁=Ph, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 219. m=1, n=2. R₁=Ph, R₂=4-BrPh, R₃=Me, R₄=H, R₅=H 220. m=1, n=2, R₁=Ph, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 221. m=1, n=2, R₁=Ph, R₂=4-NH₂Ph, R₃=Me, R₄=H, R₅=H 222. m=1, n=2, R₁=Ph, R₂=4-NO₂Ph, R₃=Me, R₄=H, R₅=H 223. m=1, n=2, R₁=Ph, R₂=4-OHPh, R₃=Me, R₄=H, R₅=H 224. m=1, n=2, R₁=Ph, R₂=4-OHPh, R₃=Me, R₄=H, R₅=H 225. m=1, n=2, R₁=Ph, R₂=4-OHPh, R₃=Me, R₄=3-(4-hydroxyphenyl)propyl, R₅=H 226. m=1, n=2, R₁=Ph, R₂=4-OHPh, R₃=Me, R₄=3-(4-hydroxyphenyl)propyl, R₅=H

Definitions

The term “aryl” refers to aromatic groups having 6 to 24 carbon atoms, and “substituted aryl” refers to aryl groups further bearing one or more substituents. The aryl groups may have one ring or two or more fused rings.

The term “alkyl” refers to straight or branched chain alkyl radicals having 1 to 19 carbon atoms, and “substituted alkyl” refers to alkyl radicals further bearing one or more substituents.

The term “lower alkyl” refers to straight or branched chain alkyl radicals having in the range of 1 to 4 carbon atoms.

The term “cycloalkyl” refers to cyclic ring-containing moieties containing 3 to 8 carbon atoms, and “substituted cycloalkyl” refers to cycloalkyl moieties further bearing one or more substituents.

The term “alkenyl” refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond and having 2 to 19 carbon atoms, and “substituted alkenyl” refers to alkenyl groups further bearing one or more substituents.

The term “heteroaryl” refers to aromatic groups containing one or more heteroatoms as part of the ring structure and having 3 to 24 carbon atoms, and “substituted heteroaryl” refers to heteroaryl moieties further bearing one or more substituents. Heteroaryl groups may have one ring or two or more fused rings.

The term “heterocyclic” refers to cyclic moieties containing one or more heteroatoms as part of the ring structure and having 3 to 24 carbon atoms, and “substituted heterocyclic” refers to heterocyclic moieties further bearing one or more substituents. Heterocycle groups may have one ring or two or more fused rings.

The term “linked” refers to a first moiety (e.g., an aryl group or a heteroaryl group) that is directly bound to a second moiety (e.g., a second aryl group or heteroaryl group) via a single bond.

Pharmaceutically acceptable salts include Cl⁻, Br⁻, I⁻, NO₂ ⁻, HSO₄ ⁻, SO₄ ⁻, HPO₄ ⁻, PO₄ ²⁻, ethanesulfonate, trifluromethane sulfate, p-toluenesulfonate, benzenesulfonate, salicylate, proprionate, ascorbate, aspartate, fumarate, galactarate, maleate, citrate, glutamate, glycolate, lactate, malate, maleate, tartrate, oxalate, succinate, or similar acid addition salts. The above salt forms may be in some cases hydrates or solvates with alcohols and other solvents.

Pharmaceutical Compositions

Also disclosed herein are pharmaceutical compositions comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients. For example, the pharmaceutical composition may include a pharmaceutically acceptable additive, such as a stabilizer, buffer, salt, preservative, filler, flavor enhancer and the like, as known to those skilled in the art. Representative buffers include phosphates, carbonates, and citrates. Exemplary preservatives include EDTA, EGTA, BHA, and BHT.

The pharmaceutical composition disclosed herein may be administered by inhalation (i.e., intranasally as an aerosol or inhalation solution or suspension); topically (i.e., in the form of an ointment, cream or lotion); orally (i.e., in solid or liquid form (tablet, capsule, gel cap, time release capsule, powder, solution, or suspension in aqueous or non-aqueous liquid); intravenously as an infusion or injection (i.e., as a solution, suspension or emulsion in a pharmaceutically acceptable carrier); or subcutaneously as an infusion or injection (i.e., as a solution, suspension or emulsion in a pharmaceutically acceptable carrier) or as a depot formulation; transdermally (e.g., via a transdermal patch), or rectally (e.g., as a suppository).

There is no limitation in the route of administration or dosage form, and the composition may be administered in accordance with specific form of the preparation, age, sex and the other conditions of a patient, severity of disease, etc. For example, in the case of tablet, pill, solution, suspension, emulsion, granule and capsule, the composition is orally administered. In the case of injection, the composition is intravenously administered alone or in a mixture with conventional replacement fluid such as glucose and amino acids, and if necessary, and the preparation alone may be also administered intramuscularly, intracutaneously, subcutaneously or interperitoneally.

The compounds disclosed herein can be administered alone, combined with a pharmaceutically acceptable excipient, or co-administered with a second drug. Co-administration may provide a similar or synergistic effect. A compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered subcutaneously, intramuscularly, intravenously, transdermally, orally, intranasally, intrapulmonary, or rectally.

The dose of the pharmaceutical composition of the present invention is appropriately selected in accordance with dosage regimen, age, sex and the other conditions of a patient. The amount to be administered depends to some extent on the lipophilicity of the specific compound selected, since it is expected that this property of the compound will cause it to partition into fat deposits of the subject. The precise amount to be administered can be determined by the skilled practitioner in view of desired dosages, side effects and medical history of the patient and the like.

The pharmaceutical composition may comprise a compound of formula (I) or an enantiomer or racemate thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive or a pharmaceutically acceptable excipient.

Treatment of Drug Abuse

VMAT2 is considered as a valid target for the development of treatments for the abuse of drugs, including, for example, methamphetamine (METH), amphetamine, cocaine, methylphenidate, and opiate abuse and use disorders. For example, METH decreases vesicular DA sequestration by inhibiting vesicular uptake through VMAT2 (IC₅₀=14.9 μM) and by diffusing across the vesicular membranes to decrease the pH gradient, resulting in the loss of free energy needed for monoamine transport.

Lobelane competitively inhibits [³H]DA uptake into rat brain vesicles via interaction with VMAT2 (K_(i)=45 nM), decreases METH-evoked DA overflow from rat striatal slices, and decreases METH self-administration, but does not act as a psychostinulant, suggesting that it has potential as a novel treatment for METH abuse. Nor-Lobelane (K_(i)=44 nM) is equipotent with lobelane at VMAT2 in inhibiting [³H]DA uptake.

METH can be considered as a structural fragment of lobelane/nor-lobelane, and introducing bulky substituents onto the N-atom of METH afforded compounds with increased inhibitory potency at VMAT2, reduced the psychostimulant effects of METH, diminishing its abuse potential. Importantly, these new analogs did not increase locomotor activity in rats, indicating they do not act as psychostimulants. Lee, N.-R. et al., Drug and Alcohol Dependence, “Enantiomers of (+)GZ-888 potently and selectively inhibit vesicular monoamine transporter-2 function and methamphetamine-stimulated locomotor activity,” (2016)

Treatment of a Disease or Pathology of the Central Nervous System or an Eating Disorder

Modulation of VMAT2 has potential as a therapeutic for central nervous system diseases or pathologies. Thus, VMAT2 is a target for the development of treatments for a disease or pathology of the central nervous system, including, for example, cognitive disorders, brain trauma, memory loss, psychosis, sleep disorders, obsessive compulsive disorders, panic disorders, myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Huntington's disease, attention deficit hyperactivity disorder, hyperkinetic syndrome, chronic nervous exhaustion, narcolepsy, pain, motion sickness, and/or depression.

VMAT2 is also a target for the development of treatments for eating disorders, including, for example, obesity. Compulsive eating is linked to addiction-like neuroadaptive responses in brain reward circuits. Johnson, P. M. et al., “Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats,” Nature Neuroscience, 2010, 13, 635-641. Modulation of VMAT2 may lead to reduced reward responses, diminishing overeating.

A preferred compound is a compound of formula (I), wherein the compound is 3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Another preferred compound is (S)-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine hydrochloride.

Another preferred embodiment is a pharmaceutical composition comprising 3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine or an enantiomer; racemate; or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive or a pharmaceutically acceptable excipient. A further preferred embodiment is a pharmaceutical composition comprising (S)-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine hydrochloride and a pharmaceutically acceptable additive or a pharmaceutically acceptable excipient.

Other preferred embodiments of the present invention include

or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.

Another preferred embodiment of the invention is a method of treating a disease or pathology of the central nervous system or an eating disorder in an individual in need thereof wherein the method comprises the step of administering to the individual a compound of formula (I) or a pharmnnaceutically acceptable salt thereof.

The compounds of the present invention may be used in a method of treating a disease or pathology of the central nervous system, wherein the disease may be cognitive disorders, brain trauma, memory loss, psychosis, sleep disorders, obsessive compulsive disorders, panic disorders, myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Huntington's disease, attention deficit hyperactivity disorder, hyperkinetic syndrome, chronic nervous exhaustion, narcolepsy, pain, motion sickness, and/or depression.

The compounds of the present invention may also be used in a method of treating an eating disorder. The eating disorder may be obesity.

The compounds of the present invention may be used in a method of treating one or more substance use disorders, drug dependence/abuse or withdrawal from drug dependence/abuse in an individual in need thereof. Substance use disorder and drug dependence/abuse includes dependence/abuse of psychostimulants or drugs that release dopamine. For example, the drug which the individual is using and/or dependent upon may be amphetamine, methamphetamine, and other drugs that release dopamine.

EXAMPLES

A series of VMAT2 inhibitors were synthesized and evaluated for their activity at VMAT2, dopamine transporters (DAT), and serotonin transporters (SERT) using rat striatum, hERG channels expressed by HEK-293 cells, and for their effect on METH-stimulated locomotor activity in rats. Compounds of the invention exhibited affinity at VMAT2 as well as selectivity at VMAT2 over hERG, DAT, and SERT. Further, a significant reduction of METH-stimulated locomotor activity was observed after administration of the compounds.

Example 1 Synthesis of compound 10. (S)-3-(4-methoxyphenyl)-N-(1-phenylpropen-2-yl)propan-1-amine

To a solution of phenyllithium (50 mL, 1.8 M in dibutyl ether) in THF (50 mL) was added (R)-propylene oxide (5 g) dropwise at −78° C. The resulting mixture was stirred at the same temperature for 1 hr before warmed to room temperature. After stirred at room temperature overnight, the reaction was quenched by adding saturated NH₄Cl aqueous solution. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica (hexanes/ethyl acetate 10:1 to 3:1) to afford (R)-1-phenylpropan-2-ol (10.4 g) as a colorless oil.

To a solution of (R)-1-phenylpropan-2-ol (4.16 g, 30.50 mmol) and triethylamine (7.72 g, 10.64 mL, 76.27 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (4.54 gm, 3.07 mL, 39.65 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 15 min. Dichloromethane (100 mL) was added to the mixture and then washed with water (2×150 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting light yellow oil was mixed with sodium azide (5.95 g, 91.5 mmol) in DMF (40 mL) and heated at 55° C. for 3 hrs. The reaction mixture was diluted with diethyl ether (150 mL) and washed with water (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica (hexanes/ethyl acetate 50:1 to 20:1) to afford (S)-(2-azidopropyl)benzene (4.38 g) as a colorless oil.

To a solution of (S)-(2-azidopropyl)benzene (4.0 g, 24.81 mmol) in THF (90 mL) and water (10 mL) was added triphenylphosphine (9.11 g, 34.74 mmol) at room temperature. The resulting mixture was stirred for 18 hrs and water (50 mL) was added. The resulting mixture was treated with HCl (1.0 M) to pH ˜1 and the aqueous phase was extracted with diethyl ether (3×100 mL) and dichloromethane (2×100 mL). NaOH (15%) was added dropwise to the aqueous phase to adjust the pH to about 11 and extracted with dichloromethane (5×60 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford (S)−1-phenylpropan-2-amine as a colorless oil. The crude amino product (3.03 g, 22.41 mmol) was mixed with 3-(4-methoxyphenyl)propanoic acid (4.44 g, 24.65 mmol), and HOBt (3.63 g, 26.89 mmol) in dichloromethane (60 mL) at room temperature. Triethylamine (5.67 g, 56.03 mmol) was added followed by EDCl (5.15 g, 26.89 mmol). The resulting mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (3×50 mL), and brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was chromatographed on silica (dichloromethane/ethyl acetate 10:1) to afford (S)-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propanamide (6.18 g) as a white solid. (S)-3-(4-Methoxyphenyl)-N-(1-phenylpropan-2-yl)propanamide (5.0 g, 16.81 mmol) in THF was cooled to 0° C. LAH (60 mL, 1.0 M in THF) was added dropwise and the resulted reaction mixture was heated at reflux for 6 hrs. After cooled to 0° C., water (2.28 mL) was carefully added, followed by NaOH (15%, 2.28 mL) and water (6.84 mL). The resulted mixture was warmed to room temperature and stirred for 2 hrs. Filtered over celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was chromatographed on silica (dichloromethane/methanol 30:1 to 10:1) to afford compound 10 (4.3 g) as a white solid.

Example 2 [³H]Dihydrotetrabenazine ([³H]DTBZ) Binding Assay, Vesicular Preparation

Synaptic vesicles were prepared from rat brain using a modification of a previously described procedure (Teng et al., 1998). Briefly, fresh whole brain (excluding cerebellum) was homogenized using a Teflon pestle (clearance 0.003 inches) with 7 vertical strokes at 800 rpm in 20 vol of ice-cold 0.32 M sucrose and centrifuged at 1000 g for 12 min at 4° C. The resulting supernatant (S₁) was then centrifuged at 22,000 g for 10 min at 4° C. The synaptosomal pellets (P₂) were homogenized in 18 mL of ice-cold Milli-Q water and exposed for 5 min for lysing synaptosomes. Osmolarity was restored by addition of 2 mL of 25 mM HEPES with 100 mM dipotassium tartrate (pH 7.5). Samples were centrifuged at 20,000 g for 20 min at 4° C. to remove lysed synaptosomal membranes. MgSO₄ (1 mM) was added to the supernatant (S₃), and was centrifuged at 100,000 g for 45 min at 4° C. The final vesicular pellets (P₄) were resuspended in ice-cold assay buffer (see below) providing ˜15 μg protein/100 μL, determined by the method of Bradford (1976) using bovine serum albumin as a the standard. Aliquot parts (100 μL) of suspension of vesicle membrane protein were incubated in assay buffer (25 mM HEPES, 100 mM dipotassium tartrate, 5 mM MgSO₄, 0.1 mM EDTA and 0.05 mM EGTA, pH 7.5, at 25° C.) in the presence of 3 nM [³H]DTBZ and at least 7 concentrations (1 nM-1 mM) of compound for 1 hr at room temperature. Nonspecific binding was determined in the presence of 20 μM tetrabenazine, a standard compound. Assays were performed in duplicate using a 96-well plate format. Reactions were terminated by filtration of samples on a Unifilter-96 GF/B filter plates (presoaked in 0.5% polyethylenimine), using a FilterMate harvester (Packard BioScience Co., Meriden, Conn.). After washing 5 times with 350 μL of the ice-cold wash buffer (25 mM HEPES, 100 mM dipotassium tartrate, 5 mM MgSO₄ and 10 mM NaCl, pH 7.5), filter plates were dried, sealed and each well filled with 40 μL Packard's MicroScint 20 cocktail. Bound [³H]DTBZ was measured using a Packard TopCount NXT scintillation counter with a Packard Windows NT based operating system.

Example 3 [³H]Dopamine ([³H]DA) Uptake Assay, Vesicular Preparation

Inhibition of [³H]DA uptake was conducted using isolated synaptic vesicle preparations (Teng et al., 1997). Briefly, rat striata were homogenized with 10 up-and-down strokes of a Teflon pestle homogenizer (clearance ˜0.003″) in 14 ml of 0.32 M sucrose solution. Homogenates were centrifuged (2,000 g for 10 min at 4° C.), and then the supernatants were centrifuged (10,000 g for 30 min at 4° C.). Pellets were resuspended in 2 ml of 0.32 M sucrose solution and subjected to osmotic shock by adding 7 ml of ice-cold MilliQ water to the preparation. After 1 min, osmolarity was restored by adding 900 μl of 0.25 M HEPES buffer and 900 μl of 1.0 M potassium tartrate solution. Samples were centrifuged (20,000 g for 20 min at 4° C.), and the supernatants were centrifuged (55,000 g for 1 hr at 4° C.), followed by addition of 100 μl of 10 mM MgSO₄, 100 μl of 0.25 M HEPES and 100 μl of 1.0 M potassium tartrate solution prior to the final centrifugation (100,000 g for 45 min at 4° C.). Final pellets were resuspended in 2.4 ml of assay buffer (25 mM HEPES, 100 mM potassium tartrate, 50 μM EGTA, 100 μM EDTA, 1.7 mM ascorbic acid, 2 mM ATP-Mg²⁺. pH 7.4). Aliquots of the vesicular suspension (100 μl) were added to tubes containing assay buffer, various concentrations of compound (0.1 nM-10 mM) and 0.1 μM [³H]DA in a final volume of 500 μl, and incubated at 37° C. for 8 min. Nonspecific uptake was determined in the presence of the standard compound, Ro4-1284 (10 μM). Reactions were terminated by filtration, and radioactivity retained by the filters was determined by liquid scintillation spectrometry (Tri-Carb 2100TR liquid scintillation analyzer; PerkinElmer Life and Analytical Sciences, Boston, Mass.).

Example 4

[³H]Dofetilide Binding Assay, HEK-293 Cell Membrane Preparation

[³H]Dofetilide binding assays were conducted using commercially available HEK-293 cell membranes which stably express the hERG channel. Membranes were suspended in assay buffer (50 mM Tris, 10 mM KCl, 1 mM MgCl₂, pH 7.4) prior to the experiment. Assays were performed in duplicate in a total volume of 250 μL. Aliquots of the HEK-293 cell membrane suspension which contained 5 μg membrane protein were added to tubes containing assay buffer, 5 nM [³H]dofetilide and a range of concentrations of analog (10 nM-100 μM). Nonspecific binding was determined in the presence of amitriptyline (1 mM). Samples were incubated for 1 hr. at 24° C., followed by rapid filtration. Radioactivity retained by the filters was determined by liquid scintillation spectrometry as described above for the [³H]DA uptake assay. The affinity for the [³H]dofetilide binding site on the hERG channel expressed in the HEK-293 cellular membrane was determined from the analog concentration response curves.

Example 5

[³H]DA and [³H]5-HT Uptake Assay, Synaptosomal Preparation

[³H]DA and [³H]5-HT uptake into striatal synaptosomes was determined to evaluate compound inhibition of the dopamine transporter (DAT) and the serotonin transporter (SERT), respectively. Striata from individual rats were homogenized in ice-cold sucrose solution containing 5 mM NaHCO₃ (pH 7.4), with 16 up-and-down strokes of a Teflon pestle homogenizer (clearance=0.003″). Homogenates were centrifuged at 2000 g for 10 min at 4° C., and resulting supernatants were centrifuged at 20.000 g for 17 min at 4° C. Pellets were resuspended in 2.4 mL (for DAT assays) or 1.5 mL (for SERT assays) of assay buffer (125 mM NaCl, 5 mM KCl, 1.5 mM MgSO₄, 1.25 mM CaCl₂, 1.5 mM KH₂PO₄, 10 mM alpha-D-glucose, 25 mM HEPES, 0.1 mM EDTA, 0.1 mM pargyline, 0.1 mM ascorbic acid, saturated with 95% O₂/5% CO₂, pH 7.4). Assays were performed in duplicate in a total volume of 500 μL (for DAT assays) or 250 μL (for SERT assays). Aliquots of the synaptosomal suspension (25 μL for DAT, 50 μL for SERT) were added to tubes containing assay buffer and various concentrations of analog (1 nM-100 μM), and incubated at 34° C. for 5 min. Nonspecific uptake was determined in the presence of nomifensine (10 μM) for DAT assays or fluoxetine (10 μM) for SERT assays. GBR-12935 (100 nM) was included in the assay buffer for the SERT assay to maximally inhibit [³H]5-HT uptake through DAT and isolate uptake to SERT. Samples were placed on ice, and 50 μL of 0.1 μM [³H]DA (for DAT assays) or 25 μL of 0.1 μM [³H]5-HT (for SERT assays) was added to each tube, and incubated for 10 min at 34° C. Reactions were terminated by addition of 3 mL of ice-cold assay buffer and subsequent filtration and radioactivity retained by the filters was determined by liquid scintillation spectrometry (Tri-Carb 2100TR liquid scintillation analyzer; PerkinElmer Life and Analytical Sciences, Boston, Mass.).

Exemplary compounds 1-53 were tested in [³H]dihydrotetrabenazine ([³H]DTBZ) binding assay according to Example 2 and the [³H]dopamine ([H]DA) uptake assay according to Example 3. The results of these assays are set forth in Table 1.

TABLE 1 [³H]DTBZ binding (Ki) [³H]DA uptake (Ki) Compound Structure VMAT2 (μM) VMAT2 (μM) 1

7.70 ± 1.25 0.063 ± 0.005 2

7.53 ± 2.16 0.51 ± 0.10 3

1.23 ± 0.13 0.033 ± 0.007 4

1.13 ± 0.31 0.007 ± 0.002 5

0.91 ± 0.59 0.006 ± 0.001 6

0.75 ± 0.14 0.065 ± 0.004 7

1.56 ± 0.47 0.096 ± 0.010 8

 2.2 ± 0.11 0.014 ± 0.003 9

— 0.0087 ± 0.0065 10

—  0.026 ± 0.0036 11

 0.70 ± 0.063 0.008 ± 0.001 12

— 0.006 ± 0.001 13

— 0.032 ± 0.004 14

0.081 ± 0.016  0.003 ± 0.0003 15

 0.19 ± 0.020 0.003 ± 0.002 16

0.46 ± 0.08 0.012 ± 0.003 17

0.63 0.014 ± 0.001 18

0.91 ± 0.59 0.009 ± 0.002 19

4.1 ± 0.3 0.059 ± 0.007 20

2.0 ± 0.1 0.013 ± 0.009 21

1.5 ± 0.2 0.12 ± 0.01 22

2.0 ± 0.1  0.12 ± 0.001 23

3.4 ± 0.6 0.092 ± 0.017 24

3.77 ± 0.99 0.074 ± 0.002 25

11.9 ± 1.84  0.46 ± 0.075 26

1.27 ± 0.09 0.022 ± 0.003 27

— 0.045 ± 0.004 28

— 0.020 ± 0.001 29

0.41 ± 0.14 0.011 ± 0.002 30

7.11 ± 0.82  0.27 ± 0.038 31

2.4 ± 0.1 0.062 ± 0.029 32

4.7 ± 0.4 0.030 ± 0.002 33

1.5 ± 0.2 0.060 ± 0.007 34

0.87 ± 0.03 0.010 ± 0.004 35

2.6 ± 0.4 0.047 ± 0.006 36

0.23 ± 0.06 0.072 ± 0.030 37

0.82 ± 0.27 0.033 ± 0.008 38

2.5 ± 1.6 0.069 ± 0.009 39

1.3 ± 0.3  0.010 ± 0.0002 40

1.7 ± 0.4 0.017 ± 0.003 41

5.1 ± 1.2 0.060 ± 0.007 42

2.0 ± 0.3 0.013 ± 0.004 43

1.4 ± 0.4 0.008 ± 0.002 44

 17 + 6.6 0.21 ± 0.08 45

2.8 ± 0.7 0.036 ± 0.003 46

3.8 ± 0.1  0.14 ± 0.013 47

1.1 ± 0.1 0.029 ± 0.011 48

1.60 ± 0.33 0.050 ± 0.004 49

29.8 ± 11.2 0.084 ± 0.004 50

4.81 ± 1.13 0.050 ± 0.012 51

17.2 ± 6.33  0.36 ± 0.034 52

3.2 ± 0.1 0.026 ± 0.002 53

1.5 ± 0.7 0.024 ± 0.006

As illustrated by Table 1, compounds of the invention exhibited high affinity at VMAT2. Selectivity at VMAT2 over hERG, DAT, and SERT were also observed. For example, Compound 9 exhibited a K_(i) value of 8.71±3.65 at VMAT2, and Compound 10 exhibited a K_(i) value of 25.5±3.57 nM at VMAT2. Further, both Compound 9 and Compound 10 exhibited a >30-fold selectivity at VMAT2 over hERG, DAT, and SERT.

The compounds of the invention were also evaluated for their effect on METH-stimulated locomotor activity in rats. The compounds were observed to exhibit a significant reduction of METH-stimulated locomotor activity after administration. For example, a significant reduction of METH-stimulated locomotor activity was observed after administration of Compound 9 (3 mg/kg, s.c.) and Compound 10 (17 mg/kg, s.c.).

Further exemplary Compounds 54-226 were synthesized and are illustrated in Table 2 below. An additional exemplary synthetic procedure is set forth below in Example 6.

Exemplary compounds 54-226 were tested using the [³H]dopamine ([³H]DA) uptake assay according to Example 3, and the microsomal assays according to Example 7. The results of these assays are set forth in Table 2. In addition, various exemplary compounds from among 54-226 were tested using the pharmacokinetic assays according to Example 8.

TABLE 2 VMAT2 (rat) hERG Micro- Micro- Inhibition: Binding: Micro- somal somal Mean Ki Mean Ki somal stability stability (nM) ± (nM) ± stability assays: assays: Standard Standard assays: Half- Clearance Structure Deviation Deviation Species life (hr) (ml/min/kg) 54

61.8 ± 1.69 908 ± 102 55

27.4 ± 8.93 1550 ± 630  Rat <0.1 >400 56

27.4 ± 8.93 1550 ± 630  Human 0.2 106 57

68.9 ± 13.3 4250 ± 220  58

16.6 ± 3.99 42.3 ± 8.21 59

13.1 ± 2.87 55.6 ± 7.7  60

48.3 ± 16.4 3140 ± 1550 Rat 1 30.7 61

48.3 ± 16.4 3140 ± 1550 Human 2.2 9.6 62

31.6 ± 4.66 2380 ± 1120 Rat 0.6 83 63

31.6 ± 4.66 2380 ± 1120 Human 1.8 11.6 64

16.4 ± 1.47 28.8 ± 13.7 65

112 ± 16.8 Not determined 66

32.5 ± 3.52 10100 ± 3350  Rat 1.5 30.7 67

32.5 ± 3.52 10100 ± 3350  Human >4 <10.0 68

 5.53 ± 0.567  633 ± 46.3 Human <0.1 >400 69

 5.53 ± 0.567  633 ± 46.3 Rat 0.6 76.8 70

22.5 ± 4.48 2600 ± 711  Human 0.9 23 71

22.5 ± 4.48 2600 ± 711  Rat 0.5 97.2 72

16.4 ± 2.89  516 ± 63.6 Human 0.8 26.5 73

16.4 ± 2.89  516 ± 63.6 Rat 1.1 43.7 74

8.82 ± 2.05 831 ± 187 75

22700 ± 432   Not determined Human 0.2 121 76

22700 ± 432   Not determined Rat 0.8 56 77

 21 ± 1.1 1760 ± 630  Human 1.9 11.2 78

 21 ± 1.1 1760 ± 630  Rat 0.3 167 79

19.8 ± 9.29 3441 ± 983  Rat 2.2 21.1 80

19.8 ± 9.29 3441 ± 983  Human 0.7 29.5 81

386 ± 194 Not determined Rat 0.6 83.2 82

386 ± 194 Not determined Human 0.8 26.3 83

27.7 ± 13.9 6751 ± 3617 Rat 0.4 113 84

27.7 ± 13.9 6751 ± 3617 Human 0.1 173 85

35.7 ± 7.32 1134 ± 711  Rat 0.1 335 86

35.7 ± 7.32 1134 ± 711  Human 1.1 18.1 87

  Batch A 12.7 ± 2.85 738 ± 244 Rat 3.5 13.3 88

  Batch A 12.7 ± 2.85 738 ± 244 Human 1.6 13.4 89

  Batch B 12.7 ± 2.85 738 ± 244 Human 1.5 14 90

  Batch B 12.7 ± 2.85 738 ± 244 Rat 1.9 24.9 91

36.5 ± 5.56 2200 ± 124  Rat <0.1 >400 92

36.5 ± 5.56 2200 ± 124  Human 0.2 112 93

 129 ± 7.41 Not determined 94

84.6 ± 29.1 3980 ± 3410 Rat 0.4 119 95

84.6 ± 29.1 3980 ± 3410 Human 1.6 12.9 96

78.5 ± 15.8 4070 ± 734  Rat 0.5 96.8 97

78.5 ± 15.8 4070 ± 734  Human 1.7 11.9 98

27.8 ± 5.29 17100 ± 12100 Rat <0.1 >400 99

27.8 ± 5.29 17100 ± 12100 Human 0.2 119 100

51.2 ± 12   7390 ± 1360 101

14.7 ± 9.28 4800 ± 940  Rat 0.2 253 102

14.7 ± 9.28 4800 ± 940  Human 0.6 33.9 103

378 ± 30  Not determined 104 See Compound 105 and Compound 106 105

26.8 ± 6.49 4610 ± 1010 Human 0.7 29.6 106

26.8 ± 6.49 4610 ± 1010 Rat 2.6 17.9 107

  105 ± 0.189 Not determined Rat 0.6 82.2 108

  105 ± 0.189 Not determined Human 2.2 9.6 109

  Batch A 19.2 ± 4.43 2594 ± 792  Human 0.8 25.2 110

  Batch A 19.2 ± 4.43 2594 ± 792  Rat >4 <10.0 111

  Batch B 16.7 ± 3.34 2501 ± 435  Rat 2.4 19.5 112

  Batch B 16.7 ± 3.34 2501 ± 435  Human 0.9 23.5 113

 157 ± 72.5 Not determined Human 3.3 6.3 114

 157 ± 72.5 Not determined Rat 0.5 95.9 115

  19 ± 3.81  285 ± 78.8 Human >4 <5.20 116

  19 ± 3.81  285 ± 78.8 Rat <0.1 >400 117

  Batch A 7.08 ± 1.29 206 ± 137 Rat 0.3 148 118

  Batch A 7.08 ± 1.29  206 ± 137 Human >4 <5.20 119

  Batch B 9.85 ± 1.62  130 ± 25.6 Rat 0.4 112 120

  Batch B 9.85 ± 1.62  130 ± 25.6 Human >4 <5.20 121

13.4 ± 4.8    80 ± 67.7 Human >4 <5.20 122

13.4 ± 4.8    80 ± 67.7 Rat <0.1 >400 123

43.7 ± 8.77 223 ± 199 Human 1.2 18.1 124

43.7 ± 8.77 223 ± 199 Rat 0.4 116 125

8.58 ± 3.71   82 ± 12.7 126

19.3 ± 5.14 2050 ± 773  Human 1.8 11.5 127

19.3 ± 5.14 2050 ± 773  Rat <0.1 >400 128

 963 ± 50.5 Not determined Rat >4 <10.0 129

 963 ± 50.5 Not determined Human >4 <5.20 130

634 ± 195 Not determined Human 0.6 37.3 131

634 ± 195 Not determined Rat 0.3 139 132

709 ± 172 Not determined Rat 0.3 180 133

709 ± 172 Not determined Human >4 <5.20 134

517 ± 112 Not determined Human >4 <5.20 135

517 ± 112 Not determined Rat >4 <7.00 136

 386 ± 66.4 Not determined 137

 182 ± 56.7 Not determined 138

 146 ± 41.9 Not determined Human >4 <5.20 139

 146 ± 41.9 Not determined Rat >4 <7.00 140

 132 ± 29.5 Not determined Human 1.4 14.4 141

 132 ± 29.5 Not determined Rat <0.1 >450 142

 117 ± 18.7 Not determined Rat 0.5 38.3 143

 117 ± 18.7 Not determined Human 0.5 98.1 144

 178 ± 78.9 Not determined 145

22.1 ± 6.5  506 ± 199 Rat 0.1 402 146

22.1 ± 6.5  546 ± 199 Human >4 <5.20 147

30.1 ± 14.2 1150 ± 417  148

70.3 ± 13   4700 ± 373  Rat <0.1 >400 149

70.3 ± 13   4700 ± 373  Human 0.1 162 150

39.1 ± 7.97 2340 ± 1070 Rat 0.1 540 151

39.1 ± 7.97 2340 ± 1070 Human 0.9 22.6 152

27.3 ± 12.8 5697 ± 2972 Rat 0.2 298 153

27.3 ± 12.8 5697 ± 2972 Human 1 20.5 154

69.1 ± 13.6 1910 ± 62.7  Human >4 <5.20 155

69.1 ± 13.6 1910 ± 627  Rat <0.1 >450 156

 118 ± 25.8 Not determined Human 0.1 182 157

 118 ± 25.8 Not determined Rat <0.1 >400 158

42.8 ± 8.89 1410 ± 275  Rat 0.4 120 159

42.8 ± 8.89 1410 ± 275  Human 0.1 216 160

14.3 ± 2.2  67.1 ± 14.7 Rat 0.4 119 161

14.3 ± 2.2  67.1 ± 14.7 Human >4 <5.20 162

30.5 ± 8.59 2951 ± 1360 Human 0.2 102 163

30.5 ± 8.59 2951 ± 1360 Rat <0.1 >400 164

53.3 ± 6.5  1889 ± 639  Rat 0.6 83.3 165

53.2 ± 6.5  1889 ± 639  Human >4 <5.20 166

46.5 ± 8.97 2200 ± 251  Human 0.6 34.3 167

46.5 ± 8.97 2200 ± 251  Rat 0.4 111 168

  41 ± 11.1 1780 ± 468  Human 3.5 6 169

  41 ± 11.1 1780 ± 468  Rat 0.2 200 170

6.74 ± 2.59  199 ± 64.9 Rat 1.4 34.2 171

6.74 ± 2.59  199 ± 64.9 Human 0.3 75.2 172

186 ± 127 Not determined Human 0.5 42.9 173

186 ± 127 Not determined Rat 0.4 126 174

52.1 ± 35.9 880 ± 251  Rat 0.4 126 175

52.1 ± 35.9 880 ± 251  Human >4 <5.20 176

80.7 ± 21   3770 ± 2.04  Rat 0.7 71.8 177

80.7 ± 21   3770 ± 2.04  Human >4 <5.20 178

 124 ± 29.4 5070 ± 71.4  Rat 0.5 89.3 179

 124 ± 29.4 5070 ± 71.4  Human >4 <5.20 180

48.4 ± 19.4 601 ± 195 Rat 0.2 290 181

48.4 ± 19.4 601 ± 195 Human >4 <5.20 182

52.7 ± 6.35 512 ± 126 Rat 0.1 375 183

52.7 ± 6.35 512 ± 126 Human >4 <5.20 184

9.06 ± 1.61  196 ± 30.5 Rat 0.1 452 185

9.06 ± 1.61  196 ± 30.5 Human >4 <5.20 186

72.4 ± 29.8 3320 ± 1930 Human 4.8 4.3 187

72.4 ± 29.8 3320 ± 1930 Rat 0.3 150 188

  22 ± 7.72 467 ± 280 Human 4.4 4.7 189

  22 ± 7.72 467 ± 280 Rat <0.1 >400 190

 8.28 ± 0.736 789 ± 221 Human 3.9 5.4 191

 8.28 ± 0.736 789 ± 221 Rat 0.2 195 192

11.9 ± 9.94 675 ± 127 Rat 0.6 77.2 193

11.9 ± 9.94 675 ± 127 Human 0.1 144 194

27.7 ± 7.81 791 ± 270 Rat 0.3 138 195

27.7 ± 7.81 791 ± 270 Human >4 <5.20 196

7.12 ± 1.59  402 ± 72.2 Rat 3.2 14.7 197

7.12 ± 1.59  402 ± 72.2 Human 0.5 40.4 198

 152 ± 25.6 Not determined Rat 0.1 414 199

 152 ± 25.6 Not determined Human <0.1 >400 200

15.2 ± 8.86 242 ± 76  Rat 0.3 186 201

15.2 ± 8.86 242 ± 76  Human >4 <5.20 202

 119 ± 31.8 Not determined Human 0.1 155 203

 119 ± 31.8 Not determined Rat 0.2 248 204

49.1 ± 3.51 8460 ± 4580 Human 3.6 5.8 205

49.1 ± 3.51 8460 ± 4580 Rat 0.5 90.6 206

 125 ± 25.4 Not determined 207

37.8 ± 6.59 2380 ± 517  Rat <0.1 >400 208

37.8 ± 6.59 2380 ± 517  Human <0.1 >400 209

17.1 ± 6.86 252 ± 109 210

55.4 ± 7.94 3120 ± 251  Rat 0.1 392 211

55.4 ± 7.94 3120 ± 251  Human <0.1 >400 212

22.2 ± 2.21 642 ± 168 Rat 0.1 439 213

22.2 ± 2.21 642 ± 168 Human >4 <5.20 214

6.86 ± 1.81 3043 ± 1373 Human 1.2 17.6 215

6.86 ± 1.81 3043 ± 1373 Rat 0.3 148 216

65.4 ± 23.4 4190 ± 1080 Rat 0.3 170 217

65.4 ± 23.4 4190 ± 1080 Rat 0.3 170 218

14.2 ± 2.17  421 ± 38.1 Human 2.2 9.5 219

14.2 ± 2.17  421 ± 38.1 Rat <0.1 >400 220

40.4 ± 4.72 5340 ± 5630 Rat 0.7 65.3 221 See Compound 220 222

4.97 ± 3.08 96.1 ± 28.3 Rat <0.1 >400 223

  Batch A 5.01 ± 1.72 2750 ± 1080 224

  Batch B Rat <0.1 >400 225

4.99 ± 1.19 226 See Compound 225

Example 6 Synthesis of [N-3-(4-fluorophenyl)propan-1-yl]-3-(4-aminophenyl)-fluoro-2-propylamine

2-(4-Nitrophenylmethylene)oxirane (3.58 g, 20.0 mmol, 1 eq), triethylaminetrihydro-fluoride (3.22 g, 20.0 mmole, 1 eq) and diisopropylethylamine (5.17 g, 40.0 mmol, 2 eq) were placed in a thick-walled glass pressure vial (50 ml) and heated overnight in an oil bath of 150° C. Subsequently, the reaction was cooled to ambient temperature and diluted with 100 ml of ethyl ether. The solution was extracted with 2×20 ml of 10% hydrochloric acid, 20 ml of a concentrated solution of sodium bicarbonate, and 25 ml of brine. The organic layer was separated and concentrated at 25° C. under vacuum of 40 Torr to yield 3.36 g of a mixture (9:1) of 1-fluoro-3-(4-nitrophenyl)-propan-2-ol with 2-fluoro-3-(4-nitrophenyl)-propan-1-ol, which was submitted to flash chromatography on silica gel using a solvent mixture of ethyl acetate and hexane (1:8) as an eluent. The desired product, 1-fluoro-3-(4-nitrophenyl)-propan-2-ol, was collected as the first fraction and the eluents containing it were concentrated at 35° C., and 20 Torr to yield 2.94 g (74% yield) of a light yellow, viscous, transparent oil.

A solution of 1-fluoro-3-(4-nitrophenyl)-propan-2-ol (2.76 g, 13.85 mmol, 1 eq) in 10 ml anhydrous DCM was added drop by drop by a syringe into a suspension of pyridinium chlorochromate (4.48 g, 20.8 mmol, 1.5 eq) and 4.0 g of Celite in 200 ml of anhydrous DCM while agitated well at ambient temperature. The reaction was energetically agitated at ambient temperature for 17 hours. Subsequently the mixture was diluted with 150 ml of ethyl ether, stirred for an additional 30 minutes, and filtered through a 10 cm-thick layer of 100 ml silica gel. The gel was washed with 3×25 ml of ethyl ether. The filtrates were concentrated at 35° C., and under vacuum of 40 Torr to yield 2.76 g of yellow-brown viscous oil which was purified by flash chromatography on silica-gel using a solvent mixture of ethyl acetate and hexane (1:9). The eluents colored light yellow were evaporated under vacuum at 40° C., and under 15 Torr to yield 2.56 g (93.8% yield) of the desired product, 2-fluoro-3-(4-nitrophenyl)-propan-1-ol, as light yellow viscous oil.

Into a stirred suspension of 5 g of A4 dry molecular sieves in 30 ml of anhydrous 1,2-dichloroethane were added 1-fluoro-3-(4-nitrophenyl)-propan-2-one (2.4 g, 12.1 mmol, 1.0 eq) and 1-(4-fluorophenyl)-3-propylamine (1.86 g, 12.1 mmol, 1.0 eq), and the mixture was stirred for 5 hours at ambient temperature. Subsequently, sodium borohydridetriacetate (4.53 g, 21 mmole, 1.75 eq) was added at ambient temperature, in a single portion, with intense agitation that was maintained overnight. Subsequently, the reaction mixture was diluted with 50 ml of DCM, the liquids were decanted, and the residue A4 molecular sieves were washed 5× with 10 ml of DCM each. All of the solutions were combined and placed in a separatory funnel, washed with a standard solution of sodium bicarbonate 3×20 ml, and then washed with brine 2×25 ml. The lower, organic phase was collected and dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum at 45° C., and 15 Torr to yield 3.5 g of a yellow-orange colored viscous oil, which was submitted to flash chromatography on silicagel using a solvent mixture of methanol and dichloromethane (1:10). The desired product, [N-3-(4-fluorophenyl)-propan-1-yl]-3-(4-nitrophenyl)-1-fluoro-2-propylamine (R_(f) 0.45), was collected after removal of solvents under vacuum at 35° C., and at 15 Torr as a viscous yellow oil in amount of 2.91 g (71.9% yield).

[N-3-(4-fluorophenyl)-propan-1-yl]-3-(4-nitrophenyl)-1-fluoro-2-propylamine (334 mg, 1.0 mmol, 1. eq) was suspended/dissolved in 4.0 ml of methanol placed in a 25 ml flask under septum. The flask was flushed with nitrogen, then 60 mg of 5% palladium on carbon was added under nitrogen, which was subsequently replaced with hydrogen from a balloon. The reduction was run overnight under the pressure of the hydrogen from the balloon at ambient temperature. The reaction mixture was filtered through a layer of Celite, concentrated under vacuum at 25° C., and 15 Torr to yield 272 mg (89.4% yield) of viscous, oily product of the desired [N-3-(4-fluorophenyl)-propan-1-yl]-3-(4-aminophenyl)-1-fluoro-2-propylamine.

A scheme for the synthesis of [N-3-(4-fluorophenyl)-propan-1-yl]-3-(4-aminophenyl)-1-fluoro-2-propylamine is provided below:

Example 7 Microsomal Assays

Liver microsomes (20 mg/ml protein) were purchased from Fisher scientific (female Sprague-Dawley rat microsomes, #50-722-704; pooled mix gender human liver microsomes, #50-722-516). Liver microsomes (0.73 ml) were mixed with EDTA solution (0.06 ml, 0.5 M in water) and potassium phosphate buffer (22.31 ml, 0.1M, pH 7.4, 37° C.) to make 23.1 mL of liver microsome solution (20 mg/mL liver microsome protein), 10 mM stocks of compound in DMSO were diluted with DMSO and acetonitrile (1:4, v:v) to a final concentration of 0.08 mM, 10 mM stocks of controls in DMSO (diphenhydramine HCl, verapamil HCl) were diluted to a final concentration of 0.4 mM. Each diluted compound stock (37.8 μL) was added to an aliquot of the liver microsomal solution (3 ml) and vortexed. The resulting solution was added to each of 3 wells of a master assay plate (pION Inc., MA, #110323). Each plate holds triplicate samples of two controls (0.4 mM) and up to 14 compounds (0.08 mM) in rat and human liver microsomes. Aliquots of each well of the plate (175 μl of each well) were transferred from the master plate into 5 assay plates. For 0-hr time point, pre-cooled (4° C.) internal standard (437.5 μL, 2 μM caffeine in methanol) was added to the first plate before the reaction starts. NADPH regenerating system solution A (6.05 ml, Fisher Scientific, # NC9255727) was combined with NADPH regenerating system solution B (1.21 ml, Fisher Scientific, # NC9016235) in potassium phosphate buffer (15.8 ml, 0.1 M, pH 7.4, 37° C.). The resulting NADPH solution (43.8 μl) was added to each well of all the 96-well assay plates and mixed with pipette briefly making the final protein and compound concentrations respectively: 0.5 mg/ml, 0.08 μM (0.4 μM for controls). Plates were sealed, and all plates except the 0-hr plate were incubated at 37° C., shaken at a speed of 60 rpm. A single assay plate was tested at each time point: 0.5 hr, 1 hr, 2 hr, and 4 hr. At each time point, 437.5 μL of pre-cooled internal standard was added each well of the plate to quench the reaction. The quenched plate was then centrifuged (model 5810R, Eppendorf, Westbury, N.Y.) at 3300 rpm for 15 minutes at 4° C. 120 μl supernatant was transferred to a 96-well plate, centrifuged again and analyzed by UPLC-MS (Waters Inc., Milford, Mass.). The compounds and internal standard were detected by selected ion recording (SIR).

The amount of material was measured as a ratio of peak area to the internal standard and graphed. Using the slope from the initial linear portion of this curve, the degradation rate constant is calculated using equation [1]. The rate constant was then used to calculate the compounds half-life in plasma using equation [2]. Intrinsic clearance was calculated as CLint′=(0.693/(t1/2))*(1/microsomal concentration in the reaction solution)*(45 mg microsome/gram liver)*(gram liver/kg b.w.), where microsomal concentration in the reaction solution is 0.5 mg/ml, and gram liver/kg b.w. of rat and human are 45, 32 and 20, respectively. Intrinsic clearance was also calculated as CLint′ (μL/min/mg protein)=(1000)*(0.693/(t1/2*60))/0.5.

$\begin{matrix} {k = {{- {slope}} \times 2.303}} & \lbrack 1\rbrack \\ {t_{1/2} = \frac{\ln \; 2}{k}} & \lbrack 2\rbrack \end{matrix}$

Example 8 Pharmacokinetic Assays

Animals:

Oral and intravenous dose pharmacokinetic studies were conducted in tandem in age matched female Swiss Webster mice and/or age matched male Sprague-Dawley rats purchased from Envigo-Harlan. Animals were housed in IVC cages with wood chip bedding and given food and water ad libitum. All experiments were conducted in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals, 8^(th) Ed., and were approved by the University of Kentucky's Institutional Animal Care and Use Committee.

Dose Formulation and Administration Volumes:

Hydrochloric acid salts or free base forms were used for formulation. Dose solutions of these compounds were prepared gravimetrically in 15% Kolliphor EL; 85% Saline (w:w) at concentrations allowing for administration volumes of 2.5×-10× animal body weight (kg animal body weight to mL dose volume conversion factor) depending upon compound solubility in the excipients. Drug solutions were typically warmed to 60° C. while mixing at 650 rpm for 0.25-1 h on an incubating shaker, then sterilized by filtration through 0.2 μnylon syringe filter.

Pharmacokinetic Studies:

Groups of 6 animals were dosed with formulated test compound by bolus lateral tail vein injection (iv), by oral gavage (po), or by subcutaneous injection (sc) into left hind flank. At predefined timepoints (typically 5-15 min, 20-30 min, 1 h, 3 h, 6 h, and 8-9 h), whole blood samples were collected from the saphenous vein using pre-heparinized pipet tips (n=3/timepoint from the 6 animals/group/compound having been divided into 2 groups of 3 with sampling alternated between the 2 groups). Whole blood samples were collected into microtubes and centrifuged at 4000×g for 2 min. Plasma supernatants were collected and immediately frozen on dry ice, then transferred to a −80° C. freezer to await processing for LC-MS/MS analysis. Typical dose rates were 2 mg/kg iv, 10 mg/kg po, and <30 mg/kg sc.

Calibrator and Quality Control (QC) Preparation:

Analyte spiking solutions (21× concentrated solutions in 50:50 MeOH:H₂O) were created by independent dilutions from 1 or 100 μg/mL compound solutions in 50:50 MeOH:H₂O). Plasma calibrators (usually 0.25, 0.5, 1, 5, 15, 30, 100, 400, 700, and 1000 ng/mL) were generated by the addition of 5 μL of appropriate spiking solution into 100 μL blank plasma followed by vortex mixing. Plasma QC samples (usually 0.75, 25, 500, and 850 ng/mL) were prepared in a similar manner using an independent 2^(nd) analyte stock solution. Calibrators and QCs were stored alongside experimental samples at −80° C. until analysis.

Calibrator and Quality Control (QC) Preparation:

Analyte spiking solutions (21× concentrated solutions in 50:50 MeOH:H₂O) were created by independent dilutions from 1 or 100 μg/mL compound solutions in 50:50 MeOH:H₂O). Plasma calibrators (usually 0.25, 0.5, 1, 5, 15, 30, 100, 400, 700, and 1000 ng/mL) were generated by the addition of 5 μL of appropriate spiking solution into 100 μL blank plasma followed by vortex mixing. Plasma QC samples (usually 0.75, 25, 500, and 850 ng/mL) were prepared in a similar manner using an independent 2^(nd) analyte stock solution. Calibrators and QCs were stored alongside experimental samples at −80° C. until analysis.

LC-MS/MS Analysis:

Methanolic supernatants were analyzed for compound-specific m/z molecular ion/fragment transitions and m/z 294.2→105.2 (for GZ-361b ISTD) by LC-MS/MS using multiple reaction monitoring (MRM). Analyte and internal standard contained in 5 μL sample injections (15° C. temp.; 1.5 mL 0.1% formic acid in MeOH or 1:1 MeOH:isopropanol injector rinse; 10 sec rinse dip time) were eluted from a guard-protected (2.7 μL, 3×5 mm) Agilent Poroshell 120 EC-C18 (2.7 μL, 3×50 mm; oven temp. 40° C.) analytical column with a 0.1% formic acid in water (mobile Phase-A): 0.1% formic acid in acetonitrile (mobile Phase-B) gradient. Flow rate was constant at 0.4 ml/min and the gradient usually progressed from an initial 0.5 min hold at 10% mobile Phase-B increased linearly to 90% over 3.8 min. The 90% mobile Phase-B was typically maintained for 1.2 min before returning to the initial 10% over a 1 min ramp, with re-equilibration at 10% organic for 1.5 min (7.5 min total nm time). Positive-mode ESI Turbo V® source and MS gas, temperature, and probe settings were optimized for 0.4 mL flow rate at CUR=35/ISV=4500/TEM=550/GS1=65/GS2=65/CAD=10 with the probe position=7/0.5 horizontal/vertical. Whereas compound-dependent voltage potential settings were optimized prior to analysis using infusions of ˜100 ng/mL drug standards in 50:50 mobile phase mixture (e.g., Analyte SK-4-292; DP=30, EP=10, CE=47, CXP=15). ISTD voltage potentials were set at DP=70, EP=10, CE=35 and CXP=6. Sample sequences consisted of single randomized experimental sample injections flanked by sets of blanks, calibrators and QCs with QCs interspersed, as needed, to maintain >5% total QC to experimental sample occurrence. High QCs (5,000 and 10,000 ng/mL) were inserted at end of sequence prior to second calibrator injections. Calibration curves were typically constructed by weighted (1/x²) non-linear regression analysis of analyte/ISTD concentration ratios to analyte/ISTD peak area ratios using AB SciexMultiQuant software (Ver 3.0.31721.0).

The foregoing description and examples have been set forth merely to illustrate the invention and are not meant to be limiting. Since modifications of the described embodiments incorporating the spirit and the substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the claims and equivalents thereof. 

1. A compound of formula (I):

wherein m is an integer in the range from 1 to 3; n is zero or an integer in the range from 1 to 5; R and R₂ are independently an aryl group or a heteroaryl group which may be substituted by one or more substituents; wherein substituents on R₁ and R₂ are independently selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl; isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆ cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen, and sulfur; ortho-, meta-, or para-substituted benzenephenyl; phenylethyl; amino; cycloalkylamine, isopropylamino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene, wherein one or more of the benzyl; phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; oxygen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety; selenium containing heterocyclic or heteroaryl moiety; mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; or ortho-, meta-, or para-substituted benzene substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂; R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl; 2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl; 1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl; N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl; N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl; 1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl substituted with one or more fluoro; or benzyl; R₄ is a hydrogen atom; a methyl, ethyl, propyl, isopropyl, or carbonyl group; or a methyl, ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and R₅ is hydrogen or methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 2. The compound of claim 1, wherein m is 1; n is 2; R₃ is methyl; and R₅ is a hydrogen atom or a methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 3. The compound of claim 2, wherein: R₅ is hydrogen, or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 4. The compound of claim 1, wherein m is 1; n is 2; R₁ and R₂ are independently an aryl group or a heteroaryl group which may be substituted by one or more substituents; wherein substituents on R₁ and R₂ are independently selected from the group consisting of methyl; alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; phenyl; amino; cycloalkylamine; isopropylamino; N-methylamino; N, N-dimethylamino; ethylcarboxylate; carboxamide; N-methylcarboxamide; hydroxyl; methoxy; difluoromethoxy; thiol; fluoro; chloro; bromo; iodo; trifluoromethyl; nitro; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; and a sulfur containing heterocyclic or heteroaryl moiety, wherein one or more of the phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂; R₃ is a methyl, ethyl, isopropyl, hydroxymethyl, or methyl substituted with one or more fluoro; or benzyl; and R₄ is a hydrogen atom; a carbonyl group; or a methyl, ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and R₅ is hydrogen or methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 5. The compound of claim 2, wherein R₁ is a pyridyl group; a pyrimidyl group; an unsubstituted phenyl; or a phenyl substituted with chloro, fluoro, bromo, difluoro, trifluoromethyl, methoxy, carboxamide, amino, pyridinyl, or nitro; and R₂ is a indolyl group; a pyridyl group; a pyrazolyl group; an imidazolyl group; a quinolinyl group; a methylpyrazolyl group; an unsubstituted phenyl; or a phenyl substituted with fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, carboxamide, methylcarboxamide, amine, aminoisopropyl, aminocyclobutyl dimethylamino, nitro, methylsulfonyl, methylsulfinyl, ethylcarboxylate, pyrimidinyl, pyridinyl, indolyl, thiophene, or hydroxyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 6. The compound of claim 1, wherein the compound is selected from the group consisting of invention include

or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 7. A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable additive:

wherein m is an integer in the range from 1 to 3; n is zero or an integer in the range from 1 to 5; R₁ and R₂ are independently an aryl group or a heteroaryl group which may be substituted by one or more substituents; wherein substituents on R₁ and R₂ are independently selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl; isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆ cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen, and sulfur; ortho-, meta-, or para-substituted benzenephenyl; phenylethyl; amino; cycloalkylamine, isopropylamino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene, wherein one or more of the benzyl; phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; oxygen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety; selenium containing heterocyclic or heteroaryl moiety; mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; or ortho-, meta-, or para-substituted benzene substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂; R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl; 2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl; 1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl; N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl; N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl; 1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl substituted with one or more fluoro; or benzyl; R₄ is a hydrogen atom; a methyl, ethyl, propyl, isopropyl, or carbonyl group; or a methyl, ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and R₅ is hydrogen or methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 8. The pharmaceutical composition of claim 7, wherein m is 1; n is 2; R₃ is methyl; and R₅ is a hydrogen atom or a methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 9. The pharmaceutical composition of claim 8, wherein: R₅ is hydrogen; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 10. The pharmaceutical composition of claim 7, wherein m is 1; n is 2; R₁ and R₂ are independently an aryl group or a heteroaryl group which may be substituted by one or more substituents; wherein substituents on R₁ and R₂ are independently selected from the group consisting of methyl; alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; phenyl; amino; cycloalkylamine; isopropylamino; N-methylamino; N, N-dimethylamino; ethylcarboxylate; carboxamide; N-methylcarboxamide; hydroxyl; methoxy; difluoromethoxy; thiol; fluoro; chloro; bromo; iodo; trifluoromethyl; nitro; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; and a sulfur containing heterocyclic or heteroaryl moiety, wherein one or more of the phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic moiety or heteroaryl substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂; R₃ is a methyl, ethyl, isopropyl, hydroxymethyl, or methyl substituted with one or more fluoro; or benzyl; and R₄ is a hydrogen atom; a carbonyl group; or a methyl ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and R₅ is hydrogen or methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 11. The pharmaceutical composition of claim 7, wherein R₁ is a pyridyl group; a pyrimidyl group; an unsubstituted phenyl; or a phenyl substituted with chloro, fluoro, bromo, difluoro, trifluoromethyl, methoxy, carboxamide, amino, pyridinyl, or nitro; and R₂ is a indolyl group; a pyridyl group; a pyrazolyl group; an imidazolyl group; a quinolinyl group; a methylpyrazolyl group; an unsubstituted phenyl; or a phenyl substituted with fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, carboxamide, methylcarboxamide, amine, aminoisopropyl, aminocyclobutyl, dimethylamino, nitro, methylsulfonyl, methylsulfinyl, ethylcarboxylate, pyrimidinyl, pyridinyl, indolyl, thiophene, or hydroxyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 12. The pharmaceutical composition of claim 7, wherein the compound is selected from the group consisting of

or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 13. A method of treating a substance use disorder, drug dependence/abuse or withdrawal from drug dependence/abuse in an individual in need thereof, wherein the method comprises the step of administering to the individual a compound of formula (I):

wherein m is an integer in the range from 1 to 3; n is zero or an integer in the range from 1 to 5; R₁ and R₂ are independently an aryl group or a heteroaryl group which may be substituted by one or more substituents; wherein substituents on R₁ and R₂ are independently selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD₃); tritiomethyl (CT₃); ethyl; propyl; isopropyl; C₄-C₇ straight chain or branched alkyl; C₃-C₆ cycloalkyl; C₄-C₇ alkenyl (including cis and trans geometrical forms); alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen, and sulfur; ortho-, meta-, or para-substituted benzenephenyl; phenylethyl; amino; cycloalkylamine, isopropylamidino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene, wherein one or more of the benzyl; phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; oxygen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety; selenium containing heterocyclic or heteroaryl moiety; mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; or ortho-, meta-, or para-substituted benzene substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂; R₃ is a methyl; ethyl; propyl; isopropyl; hydroxymethyl; 2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl; 1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl; N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl; N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl; 1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl substituted with one or more fluoro; or benzyl; R₄ is a hydrogen atom; a methyl, ethyl, propyl, isopropyl, or carbonyl group; or a methyl, ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and R₅ is hydrogen or methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 14. The method of claim 13, wherein: m is 1; n is 2; R₃ is methyl; and R₅ is a hydrogen atom or a methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 15. The method of claim 14, wherein R₅ is hydrogen; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 16. The method of claim 13, wherein m is 1; n is 2; R₁ and R₂ are independently an aryl group or a heteroaryl group which may be substituted by one or more substituents; wherein substituents on R₁ and R₂ are independently selected from the group consisting of methyl; alkylsulfonyl; alkylsulfinyl; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; phenyl; amino; cycloalkylamine; isopropylamino; N-methylamino; N, N-dimethylamino; ethylcarboxylate; carboxamide; N-methylcarboxamide; hydroxyl; methoxy; difluoromethoxy; thiol; fluoro; chloro; bromo; iodo; trifluoromethyl; nitro; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; and a sulfur containing heterocyclic or heteroaryl moiety, wherein one or more of the phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety substituent on R₁ or R₂ may be independently fused to R₁ or R₂ or linked to R₁ or R₂; R₃ is a methyl, ethyl, isopropyl, hydroxymethyl, or methyl substituted with one or more fluoro; or benzyl; and R₄ is a hydrogen atom; a carbonyl group; or a methyl ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and R₅ is hydrogen or methyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 17. The method of claim 13, wherein: R₁ is a pyridyl group; a pyrimidyl group; an unsubstituted phenyl; or a phenyl substituted with chloro, fluoro, bromo, difluoro, trifluoromethyl, methoxy, carboxamide, amino, pyridinyl, or nitro; and R₂ is a indolyl group; a pyridyl group; a pyrazolyl group; an imidazolyl group; a quinolinyl group; a methylpyrazolyl group; an unsubstituted phenyl; or a phenyl substituted with fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, carboxamide, methylcarboxamide, amine, aminoisopropyl, nitro, methylsulfonyl, methylsulfinyl, aminocyclobutyl, dimethylamino, ethylcarboxylate, pyrimidinyl, pyridinyl, indolyl, thiophene, or hydroxyl; or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 18. The method of claim 13, wherein the compound is selected from the group consisting of

or an enantiomer; racemate; or pharmaceutically acceptable salt thereof.
 19. The method of claim 13, wherein the pharmaceutical composition is administered to the individual by inhalation; topically; orally; intravenously as an infusion or injection; or subcutaneously as an infusion, injection, or depot formulation; transdermally; or rectally. 